Our objective is to test, in an ethnically homogenous population, the hypothesis that individual variation in the sensitivity to estrogens- caused by polymorphism in the estrogen receptor (ER) gene-affects a woman's risk of breast and endometrial cancer. Several polymorphisms in the ER gene have recently been described, but no study has adequately assessed their significance for malignant transformation. Our approach is uniquely cost-effective since it builds on two recently completed, coordinated, nationwide, population-based case-control studies of breast and endometrial cancer in Sweden (funded by NIH and American Cancer Society, respectively) encompassing women aged 50-74 with newly diagnosed breast cancer (n=3,900), endometrial cancer (n=l,000), and controls (n=3,500). Detailed information on reproductive factors and use of exogenous hormones allows the study proposed here to focus on never-users and long-term users. We will randomly select 900 breast cancer cases, 900 endometrial cancer cases, and 1,034 Controls (expecting 900 with a uterus). For analyses within categories of menopausal hormone use, this sample will be enriched with additional controls and cancer cases who were long-term users of menopausal hormones, for a total sample of 3,394 subjects. DNA for genetic analysis will be obtained in the cases from non-malignant cells in the tissue specimens, and among the controls from leucocytes in blood samples. The genetic analyses will assess polymorphisms in Xba I and Pvu II restriction sites in intron 1, a dinucleotide repeat polymorphism upstream Of the gene, and two polymorphisms in exons 3 and 4. The overall associations of these genetic variants on the risk of breast and endometrial cancer will be assessed in the random sample, with careful control for exogenous hormone use and breast cancer risk factors. Additional analyses within strata of menopausal hormone use and other risk factors will be conducted to explore differences in the effect of the polymorphisms. The study population will be large enough to ensure detection of relative risks under 2.0 in most of the overall analyses, and for most analyses among never-users of menopausal hormones.